Clinical infection is the biological end result of a number of factors, including the nature of the invading organism its intrinsic virulence, the microenvironment of the invaded tissue or organ, and the responsiveness of the host. Any means by which bacteria can be introduced into the tissues can result in an infection. However, the nature of the introduction can influence the severity of the infection and can alter the host's ability to respond. As injuries, a cutaneous laceration, for example, differs from an extensive surgical dissection, which in turn differs from a perforated gastrointestinal viscus. Similarly, a lung infection (a pneumonia) occurring in an area of atelectasis is different from a lung infection that takes place as a result of an aspiration event. Mere presence of pathogens in intact or injured areas does not comprise an infection. A certain critical mass of organisms is necessary in order to sufficiently overcome the host defenses and cause an invasive infection. This level of bacteria is usually stated to be 10.sup.5 organisms per gram of treatment. A variety of factors can influence the balance between microbial invader and host defenses sufficiently that infections develop at lower levels of bacterial exposure. Necrotic tissue or foreign bodies in a wound are termed adjuvant factors, understood to make infections likely to develop at lower concentrations. Local physiological factors such as impaired circulation also increase local susceptibility to infection. Systemic ailments like diabetes, uremia and AIDS are known to lower the host's resistance to infection, again making it easier for microbes to establish an infection in the tissues.
The severity of an infection in part relates to the extent of the injury that accompanies or precedes it. More severe injury (e.g., an extensive accidental or surgical trauma) interferes with host integrity more substantially, permitting freer access to host tissues and compromising intrinsic host defenses. The severity of an infection depends upon the number and kind of micro-organisms responsible for the infection. If a polymicrobial infection is diagnosed or suspected, early and aggressive antibiotic intervention is commonly warranted, often with broad-spectrum agents with activity against a number of possible invaders.
Certain virulence factors have been associated with specific microorganisms, making invasion carried out by these cells more destructive. Virulence factors are of three general types: 1) biological products produced and secreted by the infecting agent that attack cells in the host or that affect host homeostatic mechanisms to produce clinical disease; 2) structural components of the normal bacterial cell which, when shed within the host's internal environment or when released following death and lysis of the bacterial cell, have toxic effects on the host; 3) responses of the microorganism to antibiotics that make them resistant to these chemotherapeutic agents. Particular microorganisms characteristically manifest specific virulence factors. For example, Staphylococcus aureus produces coagulase, which acts as a powerful virulence factor. Staph. and Streptococcus species also produce leukocidins. As a further example, strains of B. fragilis produce superoxide dismutase, which converts superoxide anions to hydrogen peroxide; strains of E. coli produce catalase, which reduces hydrogen peroxide to water, thereby rendering possible a synergism between these two organisms. A wide variety of other virulence factors have been identified.
The most important structural virulence factor is bacterial endotoxin. Endotoxin is derived from the lipopolysaccharide outer membrane that is found in virtually all Gram negative bacteria. Endotoxin induces an extensive array of biological effects. It is understood directly to stimulate the complement cascade, to provoke platelet aggregation, to induce fever, to activate phagocytosis and the immune system, and to stimulate the synthesis of numerous cytokines. Kremer, et al., "Interleukin-1, -6 and tumor necrosis factor-alpha release is down-regulated in whole blood from septic patients", Acta Haemmatol. 95(3-4):268-273, 1996.
Factors relevant to host susceptibility include the ease of entry by which a microorganism first gains access to the host, the impediments placed in the microorganism's path as it spreads within the host, and the ability of the host ultimately to contain the invasion before suffering substantial injury. Certain hosts are known to be more vulnerable than others. Newborns, for example, are particularly prone to severe infections and sepsis. Similarly, pediatric patients can develop sepsis in response to bacterial infections that are much more benign in the adult population. Infections in the elderly are also more likely to progress to sepsis than similar infections in younger patients. Certain pathological conditions are also understood to increase the host's susceptibility to infections and sepsis. Severe trauma, such as that which characterizes major burns, predisposes the patient to microbial infections and sepsis to such an extent that these patients are considered immunocompromised hosts.
It would be desirable to identify those members of vulnerable populations at even more risk for overwhelming infection and its systemic consequences. For example, the newborn with a high temperature must be evaluated for foci of severe infection. This evaluation can include invasive measures such as lumbar puncture in order to rule out meningitis. Often the febrile newborn requires hospitalization and treatment with broad spectrum antibiotics until a source of the fever has been determined. If a subgroup of the newborn population could be identified as having greater risk or less risk of overwhelming infection, diagnostic and therapeutic measures could be tailored to the degree of risk. Lumbar puncture could be restricted to the high-risk infant, for example. Brik, et al., "Evaluation of febrile infants under 3 months of age: is routine lumbar puncture warranted?" Isr. J Med. Sci. 33(2):93-97, 1997. Or, for example, low risk infants could be managed as outpatients or discharged quickly from the hospital, offering an important cost-saving in this era of managed care. Durongpisitkul, et al., "The appropriateness of early discharge of hospitalized children with suspected sepsis", J. Fam. Pract. 44(1):91-96, 1997. Infants or children at particular risk for certain severe systemic infections could be treated with infection-specific agents, or could be treated earlier or more aggressively.
Host defenses represent an important variable in determining the severity of a clinical infection. Non-specific host defenses serve to limit the initial extent of microbial invasion. Examples include the epiglottis mechanism of the trachea, the vibrissae of the nasal airway, the alveolar macrophage system and the acid environment of the stomach. More specific responses are set into motion on the cellular level once tissue injury or microbial contamination take place. As part of this specific response, the phagocytic-inflammatory components of host defense are initially mobilized with trauma or with the invasion of infecting agents. Phagocytosis and inflammation are intended to contain and destroy the organisms before they gain sufficient systemic access to cause a clinically significant infection. When a small scale infection is localized by these mechanisms, the clinical phenomena of cellulitis or abscess formation result. With more extensive microbial contamination, effective local containment may not be possible. Nonetheless, such containment is the goal of the phagocytic-inflammatory system of host defense.
A multitude of cellular functions contribute to the phase of specific host defense. First and foremost, in response to microbial invasion the host sets in motion the components of inflammation. Only when the stimulus of invading microorganisms becomes sufficiently pronounced do these inflammatory responses rise to the level of clinical infection. Clinical infection then becomes recognizable through the constellation of inflammatory responses that are responsive to the presence of the microorganisms. Rather than a specific response to a particular invader, clinical infection represents a set of nonspecific inflammatory responses elicited by every injury and every microbial contamination. In the ongoing presence of bacteria, the insult is active and progressive, providing a sustained injury that drives the inflammatory response until the offending agents are eradicated.
An early component of this inflammatory response is the complement cascade. This system is understood to be activated by various mechanisms of local tissue injury or microvascular trauma and disruption, leading to the release of opsonins and chemotactic signals that are complement cleavage products having the effect of attracting phagocytes and facilitating their functioning. Mast cells release inflammatory proteins such as kinins and histamines that increase vascular permeability and thus facilitate the access of intravascular proteins and cells into the affected area. Neutrophils are the first phagocytic cells to arrive on the scene. About 24 hours afterwards, activated macrophages arrive.
Macrophages are derived from monocytes that enter the tissues from the bloodstream. Monocytes recruited into the tissues differentiate into macrophages and become activated. In the activated state, macrophages produce a large number of inflammatory and cytokine proteins. An important cytokine released by the activated macrophage is TNF, which has autocrine and paracrine effects. TNF provides auto-stimulation to monocytes and macrophages to maintain full activation. TNF further stimulates neutrophils to full activation. In acute inflammation such as that found with acute infection, the activated neutrophil acts as the primary phagocyte, responsible for ingesting and killing the invading organisms. These cells may further release free oxygen radicals and lysosomal enzymes into the tissue fluid, causing extracellular killing of pathogens. Side-effects of the release of these cellular cytotoxic products include tissue necrosis, further inflammation and the activation of the coagulation cascade. Furthermore, neutrophils themselves are killed as these processes progress. The end result of this localized response to microbial invasion, with liquified necrotic cells and necrotic tissue, is known clinically as pus.
At the perimeter of the wound, surrounding the central core of necrotic material and cellular debris, additional biological processes are taking place intended to wall off or restrict the penetration of viable microorganisms into unaffected tissues. More neutrophils are attracted from adjacent microvessels by the release of complement cleavage products and TNF. Platelets and coagulation proteins are also activated in the adjacent microcirculation, leading to localized thrombosis. Platelets activated during the process of thrombosis produce thromboxane A2 by way of the cyclooxygenase-thromboxane synthetase pathway of prostaglandin biosynthesis. Thromboxane A2 is a potent vasoconstrictor. The combination of obstruction and vasoconstriction diminishes the inflow of circulation into the localized area of infection, but also blocks the access of pathogens to the general circulation. Activated neutrophils attracted to the periphery of the wound marginate within the microvasculature, leading to endothelial damage, increased vascular permeability and subsequent exudation of cells and serum proteins into the tissue space.
These serum components that leak into the tissues from the microvessels serve the additional function of bringing the building-blocks of wound healing into the infected area, first fibrin, albumin and globulin, and later fibroblasts. Circulating fibroblasts are attracted into the tissues by the growth factors secreted by the activated macrophages within the infected area. Fibroblasts, in turn, produce collagen, a protein that is the basis of scar tissue. If an infection becomes chronic, with the host unable completely to eliminate the pathogen, the infected area ultimately becomes surrounded by a wall of scar tissue formed by the processes of wound healing. In the context of acute or chronic infection, wound healing mechanisms help prevent the escape of the pathogen from the local area into the more general system.
Macrophages provide the connection between the local containment aspect of host defense and the systemic response. Activated macrophages release numerous secretion products, including cytokines that have systemic as well as local effects. Nathan, "Secretory products of macrophages," J Clin. Invest. 79:319-326, 1987. The severity of the local inflammatory process may be extreme, due to magnitude of microbial inoculation or microbial virulence, so that the normal autocrine or paracrine mediators of inflammation come to have systemic effect. Systemic dissemination of pathogens or mediators of inflammation result in the host response termed sepsis.
Interleukin-1 (IL-1) is a cytokine released by the macrophage that can be disseminated systemically and induce a systemic response to local injury or infection. IL-1, when locally released, diffuses into the circulation, where it is ultimately carried to the hypothalamus. There, it acts to stimulate the production of prostaglandin-E which acts as an inflammatory mediator and an endogenous pyrogen. IL-1 is known to incite a variety of other systemic responses: it mobilizes neutrophils, stimulates liver production of acute phase proteins and complements, and interacts with tumor necrosis factor (TNF) to amplify the effects of TNF. Dinarello, "Interleukin-1," Rev. Infect. Disease 6:51-94, 1984. IL-1 further interacts with other cytokines and growth factors, for example mediating the sepsis induced changes in IGF and the accompanying changes in muscle protein synthesis. Lang, et al, "IL-1 receptor antagonist attentuates sepsis-induced alterations in the IGF system and protein synthesis", Am. J Physiol. 270(3 Pt 1):E430-437, 1996; Lang, et al, "Role of central IL-1 in regulating peripheral IGF-I during endotoxemia and sepsis", Am. J PhysioL 272(4 Pt 2):R956-962, 1998. IL-1 is also responsible for the increases in circulating eicosanoid levels, levels of IL-6 and levels of TNF. Slotman, et al, "Interleukin-1 mediates increased plasma levels of eicosanoids and cytokines in patients with sepsis syndrome", Shock 4(5):318-323, 1995; Slotman, et al, "Unopposed interleukin-1 is necessary for increased plasma cytokine and eicosanoid levels to develop in severe sepsis", Ann. Surg. 226(1):77-84, 1997.
When the systemic effects of host defense response accompany a microbial invasion, the condition is termed "sepsis." Standard definitions do not exist for such terms as sepsis, septicemia, septic syndrome and septic response. Most connotations of these terms associate them with severe systemic infection. Traditionally, the most common offending agents were thought to be gram negative bacteria; more recently it has been observed that patients can have characteristic responses of sepsis without a clearly identifiable inciting microbe. The term sepsis has thus come to be associated with any systemic response to overwhelming infection or other severe insult. Kelly, et al, "Is circulating endotoxin the trigger for the systemic inflammatory response syndrome seen after injury?" Ann. Surg. 225(5):530-541; discussion 542-543, 1997.
The term "systemic inflammatory response syndrome" (SIRS) has been applied to a set of responses consistent with what is commonly understood to be sepsis. American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference, "Definition for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis," Crit. Care Med. 20:864, 1992. The elements of this syndrome revolve around certain clinical findings, including temperature, heart rate, respiratory rate or PaCO2 and white cell count. SIRS criteria have been applied in prospective studies considering the prognosis of patients with septic-related diagnoses.
The SIRS criteria are thought by some authors to be too broad to have clinical value. One study followed 1101 patients admitted to intensive care units, finding about half of the admissions to have manifestations of SIRS, with 16% to have findings consistent with established sepsis, 5% to have findings consistent with severe sepsis and 6% to be in the state of septic shock. Salvo, et al., "The Italian SEPSIS study: preliminary results on the incidence and evolution of SIRS, sepsis, severe sepsis, and septic shock", Intensive Care Med. 21(Supple 2):S244-249, 1995. The mortality rates rise with the severity of the septic elements: about one-fourth of those patients with SIRS died, 36% with sepsis, 52% with severe sepsis, and 81% with septic shock. Late mortality after sepsis and septic shock is equally poor, with only 30% surviving the first year after hospital admission. Schoenberg, et al. "Outcome of patients with sepsis and shock after ICU treatment", Langenbecks Arch. Surg. 383(1):44-48, 1998.
The Salvo study introduced a set of gradations in inflammatory severity that parallels the staging system proposed by Siegel et al. in the earlier surgical literature. Siegel et al., "physiologic and metabolic correlations in human sepsis," Surg. 86:163-193, 1979. According to Siegel's system, the extent of the septic response is assessed according to four criteria: hyperdynamic cardiac parameters, reduced peripheral vascular resistance, narrowed arteriovenous oxygen difference, and abnormal serum lactic acid levels. Within this staging system, Stage A is characterized by a physiologic stress response, Stage B represents an exaggerated stress response, Stage C is the onset of septic shock and Stage D is low output failure and established shock. Individual patients do not necessarily progress sequentially from one stage to another. A patient can decompensate from Stage A to Stage C with no Stage B interval. Alternatively, with modem technology, a patient can be sustained in Stage B for a prolonged time, setting the stage for a number of sepsis-related sequelae such as multiple organ failure even though no frank shock has supervened. It would be desirable to identify those patients whose septic course is more likely to be progressive. This would allow early and aggressive therapies to be directed towards those patients who face the most dire prognoses. Horn, K. D. "Evolving strategies in the treatment of sepsis and systemic inflammatory response syndrome (SIRS)", QJM 91(4):265-277, 1998. Similarly if a patient is likely to remain in a prolonged Stage B, supportive measures can be instituted at early stages to forestall the consequences of multiple organ failure.
Alternate hypotheses have been proposed to explain the progression of sepsis and the occurrence of sepsis-related sequelae that can be as lethal as Stage D septic shock. One hypothesis suggests that the primary defect in sepsis is mitochondrial injury, whereby the mitochondria are unable to metabolize oxygen and related substrates. Mela et al., "Defective oxidative metabolism of rat liver mitochondria in hemorrhagic and endotoxin shock," Am. J. Physiol. 220:571-580, 1971. A second hypothesis focuses on the parallels between the systemic septic response and the local response to tissue infection and injury. This hypothesis is supported by an extensive body of experimental and clinical literature. According to this view, systemic complement activation and systemic macrophage activation lead to systemic neutrophil activation, in analogy to the interrelated local behaviors of complement, macrophages and neutrophils. Schirmer et al., "Complement activation produces hemodynamic changes characteristic of sepsis," Arch. Surg. 123:316-321, 1989; Schirmer et al., "Recombinant human TNF produces hemodynamic changes characteristic of sepsis and endotoxemia," Arch. Surg. 124:445-448, 1989.
When neutrophils are systemically activated, their actions are diffuse and unchanneled. Systemic neutrophil activation also entails diffuse neutrophil margination. In this situation, the neutrophils attach to the endothelium of vessels throughout the body and exert their effects on all tissues they encounter. Endothelial injury results from secretion of neutrophil products, leading to increased vascular permeability. As neutrophils attach to the endothelium and enter the tissues, they also release oxygen free radicals and lysoymal enzymes which contribute to a systemic inflammatory response. Release of these products into the bloodstream catalyzes further systemic responses. Entry of neutrophils into local tissues previously unaffected by infection allows disseminated tissue damage to take place.
Endothelial injury from the secreted products of activated neutrophils further results in platelet activation and induction of the coagulation cascade. Sutton, et al, "Endothelial structural integrity is maintained during endotoxic shock in an interleukin-1 type 1 receptor knockout mouse" Shock 7(2):105-110, 1997 Thromboxane A2 is thereupon released. As a result of these processes, plugs are formed in the microvascular system from the combination of neutrophils, platelets and fibrin. These plugs, combined with the vasoconstrictive effects of thromboxane, cause focal tissue ischemia Chang, et al., "Interleukin-1 in ischemia-reperfusion acute lung injury", Am. J. Respir. Crit. Care Med. 156(4 Pt 1):1230-1234, 1997. Focal ischemia in tissues leads to focal necrosis. Hinshaw, L. B. "Sepsis/septic shock: participation of the microcirculation: an abbreviated review", Crit. Care Med. 24(6):1072-1078, 1996. A physiological paradox comes to exist, where microcirculatory ischemia exists despite the presence of a hyperdynamic circulation.
Tissue necrosis, both locally and distantly, in its turn provides a stimulus for further inflammation. Rapid evolution of these processes can lead to the progression from Stage C sepsis to Stage D sepsis, with a fatal outcome common. Alternatively, if Stage B sepsis is prolonged in the face of these microcirculatory events, focal but disseminated tissue necrosis can extend to culminate in multiple organ failure.
It is understood that the systemic inflammatory response has beneficial effects as part of the host's immune system. Ertel, et al., "Downregulation of proinflammatory cytokine release in whole blood from septic patients", Blood 85(5):1341-1347, 1995. Cytokine release has been identified following surgical procedures, with more severe operative trauma occasioning more extensive release Pruitt et al., "Interleukin-1 and interleukin-1 antagonist [IL-IRN] in sepsis, systemic inflammatory response syndrome and septic shock," Shock 3:235-251, 1995. Conversely, defective response in cytokine production can lead to inadequate immune response to stress or infectious insult. Samson, et al., "Elevated interleukin-1 receptor antagonist levels in pediatric sepsis syndrome" J. Pediatr. 131(4):587-591, 1997. Neonates with sepsis, for example, have been found to have lower levels of serum IL-1 and higher levels of IL-1RN vs. normal controls. Atici, et al., "Serum interleukin-1 beta in neonatal sepsis", Acta Pediatr. 85(3):371-374, 1996; de Bont, et al., "Increased plasma concentrations of interleukin-1 receptor antagonist in neonatal sepsis", Pedatr. Res. 37(5):626-629, 1995.
It is therefore desirable to identify those whose interleukin immune feedback systems make them more vulnerable to overwhelming, initially occult sepsis. However, it is further recognized that an excessively vigorous systemic inflammatory response comprises the patterns of sepsis that culminate in such disastrous events as disseminated intravascular coagulation, multiple organ failure and cardiovascular collapse. Aikawa has termed the excessive production of cytokines that culminates in this generalized autoinflammatory reaction "cytokine storm." Aikawa, N. "Cytokine storm in the pathogenesis of multiple organ dysfunction syndrome associated with surgical insults" Nippon Geka Gakkai Zasshi 97(9):771-777, 1996. It would be clinically useful to identify patients at heightened risk for exaggerated inflammatory response who may therefore be prone to its undesirable sequelae.
Current understanding has highlighted the role played in systemic inflammation by various cytokines. Blackwell and Christman, "Sepsis and cytokines: current status", Br. J. Anaesth. 77(1):110-117, 1996. Excessive IL-1 production, for example, has been linked to the development of hypotension, shock, adult respiratory distress syndrome (ARDS), multiple organ failure, hematological abnormalities and death in patients and experimental animals with sepsis. Pruitt et al., supra. IL-1 and TNF have been implicated in producing the metabolic alterations found in sepsis and injury. Ling, et al., "Differential effects on interleukin-1 receptor antagonist in cytokine- and endotoxin-treated rats", Am. J Physiol. 268(2 Pt 1):E255-261, 1995. Similarly, trauma patients have been found to demonstrate elevated levels of inflammatory mediators, consistent with the clinical features of inflammation in these conditions. Endo, et al. "Plasma levels of interleukin-1 receptor antagonist (IL-1ra) and severity of illness in patients with burns", J. Med 27(1-2):57-71, 1996. Cytokines, particularly IL-1 and TNF, are identified as coordinating the cascade of interactions between leukocytes and endothelial cells which result in the types of tissue damage discussed above as characteristic of sepsis. Shanley, et al., "The role of cyotkines and adhesion molecules in the development of inflammatory injury", Mol. Med. Today 1(1):40-45, 1995. The presence of thrombin is understood to stimulate further production of IL-1 and TNF, thereby perpetuating the cycles of thrombosis and DIC that can accompany sepsis. Hoffman and Cooper, "Thrombin enhances monocyte secretion of tumor necrosis factor and interleukin-1 beta by two distinct mechanisms", Blood Cells Mol. Dis. 21(2):156-167, 1995; Gando, et al., "Cytokines, soluble thrombomodulin and disseminated intravascular coagulation in patients with systemic inflammatory response syndrome" Thromb. Res. 80(6):519-526, 1995.
Many current approaches for treating sepsis and its sequelae attempt to modulate cytokine interactions within the inflammatory cascade. Since IL-1 and TNF have been identified as circulating factors that integrate and perpetuate these effects, therapies designed to antagonize the effects of these agents can be designed to have clinical utility in ameliorating the sequences involved in sepsis. For example, IL-1 has been identified as playing an important role in Group B streptococcal sepsis and septic shock in the newborn; it is suggested that IL1-RN treatment may ameliorate the cardiovascular alterations associated with this disease in the newborn population. Vallette, et al., "Effect of an interleukin-1 receptor antagonist on the hemodynamic manifestations of group B streptococcal sepsis", Pediatr. Res. 38(5):704-708, 1995. Other data suggest, however, that specific cytokine inhibitors may not be effective in modulating inflammation induced by gram-negative bacterial products. Paris, et al., "Effect of interleukin-1 receptor antagonist and soluble tumor necrosis factor receptor in animal models of infection", J. Infect. Dis. 171(1):161-169, 1995. Therefore it would be useful to identify those diseases where cytokine modification is likely to work, and those where it is likely to be ineffective or hazardous.
It would furthermore be clinically advantageous to identify those patients with sepsis in whom early intervention strategies may forestall potentially devastating complications. For example, elevated levels of IL-1 have been identified as markers for poor prognosis in patients with ARDS, a common concomitant of sepsis. Meduri, et al., "Persistent elevation of inflammatory cytokines predicts a poor outcome in ARDS. Plasma IL-1 beta and IL-6 levels are consistent and efficient predictors of outcome over time", Chest 107(4):1062-1073, 1995. Determining whether a patient falls into the subgroup destined for a poor outcome can motivate the clinician to undertake early and perhaps more ambitious therapies for the ARDS, for example, early glucacorticoid treatment or early institution of extracorporeal membrane oxygenator. Headley, et al, "Infections and the inflammatory response in acute respiratory distress syndrome", Chest 111(5):1306-1321, 1997. Bonten, et al., "The systemic inflammatory response in the development of ventilator-associated pneumonia", Am. J. Respir. Crit. Care Med. 156(4 Pt 1): 1105-1113, 1997. Similarly, a patient at high risk for poor outcome may merit early, aggressive, continuous and/or multiple antibiotic treatment. Mercer-Jones, et al., "Continuous antibiotic treatment for experimental abdominal sepsis: effects on organ inflammatory cytokine expression and neutrophil sequestration" Br. J. Surg. 85(3):385-389, 1998. Steroids may be indicated to treat the global inflammatory response in those patients who are identified as inflammation overreactors. Jones and Lowes, "The systemic inflammatory response syndrome as a predictor of bacteraemia and outcome from sepsis", QJM 89(7):515-522, 1996. Lefering and Neugebauer, "Steroid controversy in sepsis and septic shock: a meta-analysis", Crit. Care Med. 23(7):1294-1303, 1995. Plasmapherisis may be appropriate to remove the inflammatory elements from the septic patient's bloodstream in those who are prone to exaggerated inflammatory response. Haupt, et al., "Selective cytoldne release induced by serum and separated plasma from septic patients", Eur. J Surg. 162(10):769-776, 1996; Stegmayr, B. G. "Plasmapheresis in severe sepsis or septic shock", Blood Purif. 14(1):94-101, 1996. Manipulating the complement system may provide an additional strategy for treating the patient with severe inflammatory response in sepsis. Kirschfink M. "Controlling the complement system in inflammation", Immunopharmacology 38(1-2):51-62, 1997. Or, realizing the additional inflammatory burden imposed by surgery in certain septic patients may further provide the clinician information about the timing of surgical interventions in sepsis, and will guide the clinician in possible forms of adjuvant therapy.
Recognizing these potential prognostic and therapeutic implications of cytokine release has led investigators and clinicians to measure cytokine levels and try to correlate them with clinical situations. van der Poll, et al, "Anti-inflammatory cytokine responses during clinical sepsis and experimental endotoxernia: sequential measurements of plasma soluble interleukin (IL)-1 receptor type II, IL-10, and IL-13", J. Infect. Dis. 175(1):118-122, 1997. For example, IL-1ra has been measured in high risk neonates and noted to be elevated one or more days before the onset of clinical sepsis (Kuester, H. et al., (1998) The Lancet 352:1271-1277). Unfortunately, under varying clinical circumstances, there has been marked variability in the data. For example, during the development of organ failure and death as a result of intra-abdominal sepsis, levels of proinflammatory mediators and their endogenous antagonists vary considerably. Wakefield, et al., "Proinflammatory mediator activity, endogenous antagonists and the systemic inflammatory response in intra-abdominal sepsis. Scottish Sepsis Intervention Group", Br. J. Surg. 85(6):818-825, 1998. Some authors find that IL-1 levels correlate positively with poor prognosis in sepsis, (Thijs and Hack, "Time course of cytokine levels in sepsis", Intensive Care Med. 21(Suppl. 2):S258-263, 1995), while others fail to find this correlation. Goldie, et al., "Natural cytokine antagonists and endogenous antiendotoxin core antibodies in sepsis syndrome", JAMA 274(2):172-177, 1995.
A means for measuring a patient's propensity for exaggerated inflammatory response as an indicator of his or her response to septic stimuli is needed.